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- PDB-6itm: Crystal structure of FXR in complex with agonist XJ034 -

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Basic information

Entry
Database: PDB / ID: 6itm
TitleCrystal structure of FXR in complex with agonist XJ034
Components
  • Bile acid receptor
  • HD3 Peptide from Nuclear receptor coactivator 1
KeywordsTRANSCRIPTION / FXR / agonist / non-alcoholic liver disease / docking screening
Function / homology
Function and homology information


regulation of urea metabolic process / intracellular bile acid receptor signaling pathway / chenodeoxycholic acid binding / positive regulation of phosphatidic acid biosynthetic process / positive regulation of glutamate metabolic process / positive regulation of ammonia assimilation cycle / bile acid receptor activity / regulation of low-density lipoprotein particle clearance / intracellular triglyceride homeostasis / cellular response to bile acid ...regulation of urea metabolic process / intracellular bile acid receptor signaling pathway / chenodeoxycholic acid binding / positive regulation of phosphatidic acid biosynthetic process / positive regulation of glutamate metabolic process / positive regulation of ammonia assimilation cycle / bile acid receptor activity / regulation of low-density lipoprotein particle clearance / intracellular triglyceride homeostasis / cellular response to bile acid / negative regulation of very-low-density lipoprotein particle remodeling / negative regulation of interleukin-1 production / regulation of bile acid biosynthetic process / regulation of insulin secretion involved in cellular response to glucose stimulus / cellular response to organonitrogen compound / toll-like receptor 9 signaling pathway / negative regulation of monocyte chemotactic protein-1 production / intracellular receptor signaling pathway / bile acid metabolic process / nitrogen catabolite activation of transcription from RNA polymerase II promoter / labyrinthine layer morphogenesis / regulation of thyroid hormone mediated signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / cell-cell junction assembly / positive regulation of female receptivity / regulation of cholesterol metabolic process / bile acid binding / bile acid signaling pathway / negative regulation of interleukin-2 production / cellular response to fatty acid / hypothalamus development / male mating behavior / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / positive regulation of interleukin-17 production / positive regulation of insulin secretion involved in cellular response to glucose stimulus / intracellular glucose homeostasis / negative regulation of interleukin-6 production / estrous cycle / negative regulation of type II interferon production / cellular response to Thyroglobulin triiodothyronine / negative regulation of tumor necrosis factor production / Synthesis of bile acids and bile salts / negative regulation of tumor necrosis factor-mediated signaling pathway / fatty acid homeostasis / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / nuclear retinoid X receptor binding / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / response to retinoic acid / negative regulation of canonical NF-kappaB signal transduction / positive regulation of insulin receptor signaling pathway / histone acetyltransferase activity / Recycling of bile acids and salts / regulation of cellular response to insulin stimulus / histone acetyltransferase / Notch signaling pathway / cellular response to hormone stimulus / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / positive regulation of neuron differentiation / RORA activates gene expression / lactation / Regulation of lipid metabolism by PPARalpha / cerebellum development / cholesterol homeostasis / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / nuclear receptor coactivator activity / Activation of gene expression by SREBF (SREBP) / response to progesterone / nuclear estrogen receptor binding / transcription coregulator binding / nuclear receptor binding / hippocampus development / RNA polymerase II transcription regulatory region sequence-specific DNA binding / euchromatin / SUMOylation of intracellular receptors / Heme signaling / mRNA transcription by RNA polymerase II / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / cerebral cortex development / negative regulation of inflammatory response / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / male gonad development / nuclear receptor activity / Circadian Clock / response to estradiol / HATs acetylate histones / DNA-binding transcription activator activity, RNA polymerase II-specific / Estrogen-dependent gene expression / cellular response to lipopolysaccharide / transcription regulator complex / sequence-specific DNA binding / transcription by RNA polymerase II / cell differentiation
Similarity search - Function
Bile acid receptor, ligand binding domain / Thyroid hormone receptor / Nuclear receptor coactivator 1 / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator / DUF1518 / Nuclear receptor coactivator, receptor-binding domain ...Bile acid receptor, ligand binding domain / Thyroid hormone receptor / Nuclear receptor coactivator 1 / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator / DUF1518 / Nuclear receptor coactivator, receptor-binding domain / Nuclear receptor coactivator / Steroid receptor coactivator / Unstructured region on nuclear receptor coactivator protein / PAS domain / Nuclear receptor coactivator, interlocking / Helix-loop-helix DNA-binding domain superfamily / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / PAS fold / PAS fold / PAS domain / PAS repeat profile. / PAS domain / PAS domain superfamily / Retinoid X Receptor / Retinoid X Receptor / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type / Zinc finger, C4 type (two domains) / Nuclear hormone receptors DNA-binding domain profile. / c4 zinc finger in nuclear hormone receptors / Nuclear hormone receptor, ligand-binding domain / Nuclear hormone receptor-like domain superfamily / Ligand-binding domain of nuclear hormone receptor / Nuclear receptor (NR) ligand-binding (LBD) domain profile. / Ligand binding domain of hormone receptors / Zinc finger, NHR/GATA-type / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-AWL / Nuclear receptor coactivator 1 / Bile acid receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsZhang, H. / Wang, Z.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China81603027 China
CitationJournal: J.Chem.Inf.Model. / Year: 2020
Title: Pose Filter-Based Ensemble Learning Enables Discovery of Orally Active, Nonsteroidal Farnesoid X Receptor Agonists.
Authors: Xia, J. / Wang, Z. / Huan, Y. / Xue, W. / Wang, X. / Wang, Y. / Liu, Z. / Hsieh, J.H. / Zhang, L. / Wu, S. / Shen, Z. / Zhang, H. / Wang, X.S.
History
DepositionNov 23, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 27, 2019Provider: repository / Type: Initial release
Revision 1.1Jun 10, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 22, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Bile acid receptor
B: HD3 Peptide from Nuclear receptor coactivator 1
C: Bile acid receptor
D: HD3 Peptide from Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,2246
Polymers59,4784
Non-polymers7462
Water59433
1
A: Bile acid receptor
B: HD3 Peptide from Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,1123
Polymers29,7392
Non-polymers3731
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1120 Å2
ΔGint-5 kcal/mol
Surface area11810 Å2
MethodPISA
2
C: Bile acid receptor
D: HD3 Peptide from Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,1123
Polymers29,7392
Non-polymers3731
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1130 Å2
ΔGint-3 kcal/mol
Surface area12060 Å2
MethodPISA
Unit cell
Length a, b, c (Å)101.484, 130.192, 37.654
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11chain A
21(chain C and (resid 258 through 469 or resid 473 through 485 or resid 501))
12chain B
22chain D

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
111GLUGLUVALVALchain AAA258 - 48512 - 239
211GLUGLUARGARG(chain C and (resid 258 through 469 or resid 473 through 485 or resid 501))CC258 - 46912 - 223
221HISHISVALVAL(chain C and (resid 258 through 469 or resid 473 through 485 or resid 501))CC473 - 485227 - 239
231AWLAWLAWLAWL(chain C and (resid 258 through 469 or resid 473 through 485 or resid 501))CF501
112ASPASPASPASPchain BBB2 - 132 - 13
212ASPASPASPASPchain DDD2 - 132 - 13

NCS ensembles :
ID
1
2

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Components

#1: Protein Bile acid receptor / Farnesoid X-activated receptor / Farnesol receptor HRR-1 / Nuclear receptor subfamily 1 group H ...Farnesoid X-activated receptor / Farnesol receptor HRR-1 / Nuclear receptor subfamily 1 group H member 4 / Retinoid X receptor-interacting protein 14 / RXR-interacting protein 14


Mass: 27949.084 Da / Num. of mol.: 2 / Mutation: E281A, E354A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR1H4, BAR, FXR, HRR1, RIP14 / Plasmid: pRHisMBP / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q96RI1
#2: Protein/peptide HD3 Peptide from Nuclear receptor coactivator 1 / SRC-1 HD3


Mass: 1790.026 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15788, histone acetyltransferase
#3: Chemical ChemComp-AWL / 1-adamantyl-[4-(5-chloranyl-2-methyl-phenyl)piperazin-1-yl]methanone


Mass: 372.931 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H29ClN2O / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 33 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.09 Å3/Da / Density % sol: 41.18 % / Mosaicity: 0.442 ° / Mosaicity esd: 0.006 °
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.2M Ammonium acetate, 0.1M Bis-Tris pH 6.5, 25% w/v Polyethylene glycol 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.97894 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 11, 2018
RadiationMonochromator: double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97894 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 18007 / % possible obs: 99.8 % / Redundancy: 8.9 % / Rmerge(I) obs: 0.06 / Rpim(I) all: 0.021 / Rrim(I) all: 0.064 / Χ2: 0.937 / Net I/σ(I): 10.8 / Num. measured all: 159545
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.5-2.598.80.8317410.770.2970.8830.94399.8
2.59-2.699.30.60317920.8960.210.6390.9799.9
2.69-2.829.40.41917360.9430.1460.4450.93799.9
2.82-2.969.20.28917640.9730.1010.3070.96899.8
2.96-3.1590.18317980.9850.0650.1950.95499.9
3.15-3.398.80.10617830.9930.0380.1130.96599.9
3.39-3.737.90.06617840.9960.0240.070.97199.3
3.73-4.279.30.04218000.9980.0140.0440.938100
4.27-5.3890.03418560.9980.0120.0360.9499.9
5.38-507.90.02819530.9990.010.030.77499.8

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Processing

Software
NameVersionClassification
PHENIX1.14_3260refinement
DENZOdata reduction
SCALEPACKdata scaling
PDB_EXTRACT3.24data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4QE6

4qe6
PDB Unreleased entry


Resolution: 2.5→47.278 Å / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 24.78 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2418 870 5 %RANDOM
Rwork0.1918 16524 --
obs0.1943 17394 96.58 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 140.89 Å2 / Biso mean: 45.246 Å2 / Biso min: 11.17 Å2
Refinement stepCycle: final / Resolution: 2.5→47.278 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3919 0 52 33 4004
Biso mean--66.18 34.47 -
Num. residues----477
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2168X-RAY DIFFRACTION9.663TORSIONAL
12C2168X-RAY DIFFRACTION9.663TORSIONAL
21B122X-RAY DIFFRACTION9.663TORSIONAL
22D122X-RAY DIFFRACTION9.663TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.5005-2.65710.31431260.236224381
2.6571-2.86230.29361310.2235278499
2.8623-3.15020.2831560.21762804100
3.1502-3.6060.24521630.19952795100
3.606-4.54250.22391410.17062876100
4.5425-47.2780.20121530.1743022100
Refinement TLS params.Method: refined / Origin x: 35.0296 Å / Origin y: 16.1117 Å / Origin z: 9.5404 Å
111213212223313233
T0.1772 Å20.0373 Å2-0.0018 Å2-0.1535 Å2-0.0351 Å2--0.1156 Å2
L1.9026 °20.6075 °20.1515 °2-0.4046 °2-0.0333 °2--0.0653 °2
S-0.0199 Å °-0.0379 Å °-0.1011 Å °0.0258 Å °0.0358 Å °-0.0991 Å °0.0071 Å °-0.0038 Å °-0.0099 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA258 - 485
2X-RAY DIFFRACTION1allA501
3X-RAY DIFFRACTION1allB2 - 13
4X-RAY DIFFRACTION1allC258 - 485
5X-RAY DIFFRACTION1allC501
6X-RAY DIFFRACTION1allD2 - 13
7X-RAY DIFFRACTION1allS1 - 33

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